Methionine is one of the human body's essential amino acids and is widely used as an additive for animal feed. It is also used as a starting material for pharmaceutical products. Methionine acts as a precursor for compounds such as choline (lecithin) and creatine. It is also a synthesis starting material for cysteine and taurine.
S-Adenosyl-L-Methionine (SAM) is a derivative of L-Methionine and is involved in the synthesis of various neurotransmitters in the brain. L-Methionine and/or SAM inhibit(s) the accumulation of lipids in the body and improves blood circulation in the brain, heart and kidneys. L-Methionine may also be used to aid digestion, detoxification and excretion of toxic substances or heavy metals such as lead. It has an anti-inflammatory effect on bones and joint diseases and is also an essential nutrient for the hair, thereby preventing the premature undesired loss thereof.
Methionine is already known to be prepared industrially by chemical routes from petrochemical-derived starting materials, as described for example in the documents FR2903690, WO2008006977, US2009318715, U.S. Pat. No. 5,990,349, JP19660043158 and WO9408957. Aside from the fact that these preparation processes do not fall within a process of sustainable development, these chemical routes have the drawback of producing an equal mixture of the two L and D enantiomers.
Completely biological syntheses by bacterial fermentation have been proposed in the literature, with the advantage of only producing the L enantiomer of methionine, as described for example in international applications WO07077041, WO09043372, WO10020290 and WO10020681. Nonetheless, the absence of large-scale industrial implementation to date leads to the assumption that the performance and/or cost price of these processes remain unsatisfactory.
Mixed chemical/biological processes have recently been successfully industrialized jointly by the company CJ Cheil-Jedang and the applicant, in which an L-methionine precursor is produced by bacterial fermentation and then reacts enzymatically with methyl mercaptan to produce L-methionine exclusively (cf. WO2008013432 and/or WO2013029690). While these processes have high levels of performance, they require the on-site synthesis of methyl mercaptan, which in turn requires the synthesis of hydrogen by steam methane reforming, the synthesis of hydrogen sulfide by hydrogenation of sulfur and the synthesis thereof from methanol and hydrogen sulfide; that is to say, very large equipment which is not very compatible with industrial extrapolation on a more modest scale in terms of annual production than that which already exists.
There therefore remains a need to produce L-methionine by a mixed process in which the equipment required for the synthesis of methyl mercaptan is smaller than for a synthesis starting from hydrogen, hydrogen sulfide and methanol. It is within this perspective that the present invention comes.
Indeed, the present invention proposes replacing methyl mercaptan in the process summarized below (WO2008013432 and/or WO2013029690) with dimethyl disulfide (DMDS):

Here, methyl mercaptan (MeSH) is used directly in the second step. The present invention proposes substituting methyl mercaptan with the product of the enzymatic hydrogenolysis of dimethyl disulfide in a prior step or combining everything in a “one pot” reaction, in which glucose and DMDS produce L-méthionine.
The following elements can be found in the prior art in relation to the synthesis of methyl mercaptan from dimethyl disulfide.
Patent application EP0649837 proposes a process for the synthesis of methyl mercaptan by catalytic hydrogenolysis, with transition metal sulfides, of dimethyl disulfide with hydrogen. Although this process is efficient, it requires relatively high temperatures of the order of 200°C to obtain industrially advantageous levels of productivity.
Those skilled in the art also know that it is possible to prepare methyl mercaptan by acidification of an aqueous solution of sodium methyl mercaptide (CH3SNa). This method has the major drawback of producing large amounts of salts, such as sodium chloride or sodium sulfate, depending on whether hydrochloric acid or sulfuric acid is used. These saline aqueous solutions are often very difficult to treat and the traces of foul-smelling products which remain mean that this method cannot be readily envisaged on the industrial scale.
It has now been found that it is possible to prepare methyl mercaptan by enzymatic reduction of dimethyl disulfide (DMDS) during a step prior to the synthesis of the L-methionine and it has also been found, surprisingly, that it is possible to carry out this enzymatic reduction of DMDS during the synthesis of the L-methionine.